Premenstrual dysphoric disorder:current status of treatmentFrancesco Bianchi-Demicheli, Frank Lüdicke, Hervé Lucas, Didier Chardonnens

Clinic of Infertility and Gynaecological Endocrinology, Department of Obstetrics and Gynaecology, Geneva University Hospitals, Geneva, Switzerland

Premenstrual dysphoric disorder (PMDD) hasalso been referred to as late luteal phase dysphoricdisorder and simply premenstrual syndrome(PMS) [1]. The essential symptoms are markedlydepressed mood, appreciable anxiety, pronouncedaffective lability, and decreased interest in activi-ties [2]. For a precise definition of the syndromethese symptoms should have regularly occurredduring the last week of the luteal phase in mostmenstrual cycles during the past year. They shouldalso remit within a few days of the onset of menses(follicular phase) and are always absent in the weekfollowing menses [2]. The research criteria forPMDD are summarised in table 1.

In the DSM-IV, the Diagnostic and StatisticalManual of Mental Disorders, PMDD is includedin category F39 (296.90) “depressive disorder nototherwise specified” and replaces the “late lutealphase dysphoric disorder” of the previous version,DSM-III-R, which included it in the category“unspecified mental disorder”. It is estimated thatat least 75% of women report minor or isolatedpremenstrual changes, and some studies suggestthat 3–8% of women experience symptoms meet-ing the criteria for PMDD [2, 3]. According toMimoun, only one woman out of eight consul-

ting for PMS presents with a PMDD meeting theDSM-IV criteria [4].

The causes of PMDD have not been clearlyelucidated and have been attributed to hormonalchange, neurotransmitters, prostaglandins, diet,drugs, and lifestyle, thus rendering treatment dif-ficult [5].

The disorder could result from an abnormallyhigh oestrogen-to-progesterone ratio [1]. It hasbeen suggested that the biogenic amine neurons ofaffected women are abnormally influenced by hor-monal changes and that the disorder is an exampleof a chronobiological phase disturbance [1].

In addition to biological theories, social andpersonal issues relating to menstruation and wom-anhood may affect the symptoms in individualpatients [1]. To understand a woman’s feelingsduring the premenstrual period it is necessary totake into account her personal history and the psy-chosocial factors involved, such as social and cul-tural beliefs and mother-daughter communication[6]. In psychoanalytical theory the premenstrualsyndrome was associated with an ambivalent preg-nancy desire and unconscious conflicts relating tosexual preference [6].

Among the various treatments proposed to

Objective: Premenstrual dysphoric disorder(PMDD), also referred to as premenstrual syn-drome (PMS), is a recurrent luteal-phase condi-tion involving regular occurrence, prior to theonset of menstrual bleeding, of a cluster of symp-toms of sufficient severity to result in the deterio-ration of interpersonal relationships and normalactivity. Several treatment options for PMDD withvarying degrees of efficacy have been proposed.The literature is reviewed and treatments ofproven efficacy are reported.

Study design and methods: A MEDLINE/Cochrane Library search for all studies on PMSand PMDD published between 1983 and 2001 wasperformed. Only randomised trials were included.

Results: Several treatments appear to be effec-tive. Among these are increased physical activity,dietary change, mineral salt supplementation andovulation inhibitors. The most effective seems tobe administration of selective inhibitors of sero-tonin reuptake (SSRIs).

Conclusion: Therapy should begin with non-medicated approaches and pharmacologicaltreatment should only be envisaged if symptomspersist.

Key words: premenstrual dysphoric disorder; pre-menstrual syndrome

574Original article S W I S S M E D W K LY 2 0 0 2 ; 1 3 2 : 5 7 4 – 5 7 8 · w w w. s m w. c h

Peer reviewed article

Summary

Introduction

No financial support to declare.

S W I S S M E D W K LY 2 0 0 2 ; 1 3 2 : 5 7 4 – 5 7 8 · w w w. s m w. c h 575

date, some have been shown to be effective andothers have no proven clinical efficacy. The aim ofthis article is to review the literature on therapeu-

tic options and identify the treatments of provenclinical efficacy.

In most menstrual cycles during the past year, five (or more) of the following symptoms were present for most of the time during the last week of the luteal phase, began to remit within a few days after the onset of the follicular phase, and were absent in the week postmenses, with at least one of the symptoms being either (1), (2), (3) or (4):

(1) markedly depressed mood, feelings of hopelessness, or self-deprecating thoughts

(2) marked anxiety, tension, feelings of being “keyed up,” or “on edge”

(3) marked affective lability (eg, feeling suddenly sad or tearful or increased sensitivity to rejection)

(4) persistent and marked anger or irritability or increased interpersonal conflicts

(5) decreased interest in usual activities (eg, work, school, friends, hobbies)

(6) subjective sense of difficulty in concentrating

(7) lethargy, easy fatigability, or marked lack of energy

(8) marked change in appetite, overeating, or specific food cravings

(9) hypersomnia or insomnia

(10) a subjective sense of being overwhelmed or out of control

(11) other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation of “bloating,” weight gain

The disturbance markedly interferes with work or school or with usual social activities and relationships with others (e.g., avoidance of social activities, decreased productivity and efficiency at work or school).

The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although it may be superimposed on any of these disorders).

Criteria A, B, and C must be confirmed by prospective daily ratings during at least two consecutive symptomatic cycles. (The diagnosis may be made provisionally prior to this confirmation.)

Table 1

DSM-IV researchcriteria for premen-strual dysphoricdisorder.

Study design and methods

A systematic search of the literature in all languagesfrom 1983 to 2001 was performed by MEDLINE and theCochrane Library (CCTR, updated quarterly) using the

following key words: premenstrual syndrome, premen-strual dysphoric disorder, late luteal phase dysphoric dis-order. Only randomised trials were considered.

Results

Physical activity, nutrition, dietarysupplements

Aerobic physical exercise modifies endorphinlevels and can improve mood. Epidemiologicalstudies confirm the positive effect of physical ex-ercise on PMDD symptoms [7]. Aganoff (1994) in-vestigated the effects of regular, moderate exerciseon mood states and menstrual cycle symptoms andcompared 97 female regular exercisers with a sec-ond group of 159 female non-exercisers [8]. Mul-tivariate analyses of covariance revealed significanteffects of exercise on negative mood states andphysical symptoms.

Dietary changes often recommended as atreatment for PMDD are a reduction in salt, sugar,alcohol, and caffeine intake, with an increase incarbohydrates. Of these, only the effectiveness ofincreased carbohydrate intake has been confirmedby a controlled study [9].

In an in-hospital study Wurtman et al. (1989)compared the occurrence and coincidence of de-

pressed mood and excessive carbohydrate intake in19 patients claiming to suffer from severe psycho-logical symptoms with that in 9 control subjectsduring the early follicular and late luteal phases oftheir menstrual cycles [9]. Consumption of a car-bohydrate-rich, protein-poor evening test mealduring the late luteal phase improved depression,tension, anger, confusion, sadness, fatigue, alert-ness and calmness scores among patients withPMDD.

Calcium and magnesium supplements havebeen shown to have a favourable clinical effect onphysical (fluid retention) and behavioural (moodchange) symptoms in PMDD [10, 11]. A double-blind randomised study in 38 women has demon-strated the clinical efficacy of magnesium supple-mentation in the treatment of mood change inPMS [12]. Tyhs Jacobs conducted a controlled,multicentre clinical trial in a group of 466 womento assess the effect of calcium carbonate on theluteal and menstrual phases in PMDD. Calcium

did indeed result in an overall 48% reduction intotal symptom scores from baseline, comparedwith a 30% reduction with placebo. It was con-cluded that calcium supplementation is a simpleand effective treatment for PMDD [11].

Vitamins (E and B6) have been recommendedfor a number of years as an effective treatment forcyclic mastalgia, particularly tocopherol. Londonet al. (1983) conducted a randomised trial among75 women to compare the effect of tocopherol withplacebo in mastodynia, and found a significant de-crease in symptoms in the tocopherol group [13].However, another randomised study showed onlyslight benefit [14]. Randomised controlled studieswith pyridoxine versus placebo showed no signifi-cant benefit [15]. Moreover, high doses of pyri-doxine were associated with peripheral neurotoxi-city.

Ovulation suppressorsThe agonist analogues of GnRH, such as

busereline (Suprefact Dépôt), gosereline (Zola-dex), or leuproreline (Lucrin Dépôt) represent aneffective treatment for PMDD [16]. This type oftreatment aims to inhibit the endogenous chrono-biological system underlying the menstrual cycle.However, due to their prolonged action, thesedrugs mimic the continued flow of GnRH, causedesensitisation of the pituitary and lower the se-cretion of gonadotropin and sexual steroids. Con-sequently, oestrogen concentrations are usuallymarkedly reduced, thus exposing patients to ahigher risk of osteoporosis where treatment is pro-longed.

Several studies have confirmed the effect ofdanazol (Danatrol), a synthetic androgen with ananti-oestrogen effect which blocks ovulation andeliminates associated symptoms [17–21]. Unfortu-nately this treatment has several important side ef-fects such as weight gain, increased pilosity andacne. Moreover, it lowers the HDL rate and is notrecommended in view of the increased cardiovas-cular risk.

Psychotropic drugsThe efficacy of psychotropic drugs has been

widely studied. The selective-reuptake inhibitors(SSRIs) such as fluoxetine (Fluctine) [22–29], ser-traline (Zoloft) [30–33], paroxetine (Deroxat)[34–36], and citalopram (Seropram) have beenshown to be effective and are the treatments ofchoice for PMDD [37, 38].

Two crossover, double-blind, placebo-con-trolled trials have shown the efficacy of sertralineat a dose of 50 mg/d or 100 mg/d during the lutealphase only [37, 38]. Daamen and Brown (1992) re-ported that a single dose of fluoxetine prescribedduring the early luteal phase was as effective as adaily dose [39]. Other studies have demonstratedthat the administration of sertraline or fluoxetineduring the premenstrual phase is effective forPMDD [31, 40].

The efficacy and safety of venlafaxine (Efexor),

a new-generation antidepressant which selectivelyinhibits serotonin and norepinephrine reuptake,has been evaluated in a placebo-controlled trial[41]. After three screening cycles, including a sin-gle-blind placebo cycle, 164 women were ran-domly assigned to double-blind treatment withvenlafaxine (50–200 mg/d) or placebo for fourmenstrual cycles. Venlafaxine was significantlymore effective than placebo in reducing PMDDsymptoms.

In a double-blind, placebo-controlled study toassess the efficacy of citalopram in the treatmentof PMDD during three menstrual cycles,Winkader et al. (1998) showed that intermittentadministration of citalopram (20 ± 10 mg/d) dur-ing the luteal phase (18 patients) and a placebo (17patients) during the follicular phase was clearlymore efficacious than placebo alone during thecomplete cycle [38]. Moreover, this treatment ap-peared to be more effective than continued ad-ministration (20 ± 10 mg/d) during the completecycle, or semi-intermittent (20 ± 10 mg/d) duringthe luteal phase and 5 mg/d during the follicularphase [38].

Alprazolam (Xanax) was investigated in sevendouble-blind, placebo-controlled studies. Fourstudies showed that it was more efficacious thanplacebo, and three others concluded that it wasonly as effective as placebo [42]. In the study byEvans et al (1998) in 20 patients, alprazolam notonly improved depressive mood state during thepremenstrual phase but also induced it in asymp-tomatic patients during the follicular phase [41].

Buspirone (Buspar), a 5-HT agonist anxi-olytic, was effective at a dose of 20 mg/d during theluteal phase [43].

PsychotherapyMorse (1999) showed during two cycles that

cognitive-behavioural-based psychotherapy cansignificantly reduce symptoms compared with agroup not undergoing therapy [44]. Over a 12-week period Blake et al. (1998) compared a groupof patients undergoing cognitive therapy once aweek with a control group. The results showed thatthe cognitive therapy was significantly more effec-tive [45]. In a randomised study comparing two dif-ferent cognitive-behavioural approaches and atherapy centred on information, Christensen(1995) reported a reduction in symptoms [46].Although none of these studies shows definitiveresults, they suggest that cognitive therapeutic ap-proaches can be useful, at least as adjuvant therapy.

PlaceboPlacebo has also been shown to be effective as

a therapeutic tool in this disorder. Many placebo-controlled studies show significant placebo effectin premenstrual symptoms [47, 48]. In a longitu-dinal study in 68 women, Magos found an initiallystrong placebo response rate but the placebo effectgradually waned [49].

In a recent study including 101 women, Free-

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1 Kaplan HI, Saddock BJ. Synopsis of Psychiatry. Baltimore:Williams & Wilkins,; 1997.

2 DSM-IV. Diagnostic and Statistical Manual of Mental Disor-ders. Paris: Masson;1996.

3 Pearlstein T, Stone AB. Premenstrual syndrome. Psychiatr.Clin. North Am 1998;21:577–90.

4 Mimoun S. Traité de gynécologie-obstétrique psychosoma-tique.Paris: Masson;1999.

5 Schellenberg R. Treatment for the premenstrual syndrome withagnus castus fruit extract:prospective, randomised, placebo con-trolled study. BMJ 2001;322:134–7.

6 Limosin F, Ades J. Psychiatric and psychological aspects ofpremenstrual syndrome. Encephale 2001;27:501–8.

7 Johnson SR. Premenstrual syndrome therapy. Clin ObstetGynecol 1998;41:405–21.

man observed in some patients with severe PMS asignificant and sustained improvement under

placebo medication, but the majority report onlypartial or no improvement [50].

Discussion

One of the major difficulties in research andtherapeutic choice is the fact that the definitions ofSPM are diverse and the diagnostic criteria havechanged over the years.

DSM-IV suggests criteria for PMDD to helpresearchers and clinicians in the correct diagnosisof the syndrome [1]. In spite of the wide dissemi-nation of diagnostic criteria in international psy-chiatric classifications, the premenstrual syndromeremains a complex and polymorphous disorder.

The aetiology of PMDD is probably multifac-torial, with the involvement of a synergic responseunderlying the disorder. PDMM appears to arisefrom various biological factors, both psychologicaland social, which are capable of influencing thecentral nervous system and the female reproduc-tive and endocrine systems [4]. The most widelystudied and frequently forwarded aetiopathogenichypothesis is serotonin dysregulation. Serotonin isclosely involved in the expression of irritability andanger, and also in the occurrence of the depressivesymptoms and specific food cravings often seen inthe premenstrual dysphoric disorder [6]. Amongtheir various effects, oestrogens increase the den-sity of serotonin receptors and enhance sensitivityto serotonin agonists [6]. There is a consensus thatthe therapeutic approach should begin with non-medicated means: a good doctor-patient relation-ship; information and completion of a daily self-evaluation calendar of symptoms; and advice onlifestyle (stress limitation, release of nervous ten-sion, appropriate diet, explaining the problem tothe family) [51].

If symptoms persist, drug therapy can be en-visaged [51]. The most effective medication for thetreatment of severe psychological or physicalsymptoms causing functional impairment are theSSRIs [52]. As reported by Dimnock et al. (2000),these are an effective first-line therapy for severePMS with low side effects [53]. Intermittent ad-ministration of SSRIs is suggested as an even moreeffective treatment [6].

However, the treatment of PMS and PMDDappears to require a strategy which will avoid ther-

apeutic changes often prompted by the patientsthemselves, exasperated by the variety of symp-toms and the consequences for their everyday andmarried lives [7].

In agreement with Johnson (1998), it wouldseem judicious as a first move to advise patients tomodify their nutritional habits by increasing car-bohydrate intake and cutting down sugar, salt, caf-feine and alcohol [7]. These dietary changes shouldbe accompanied by calcium and magnesium sup-plementation, with an increase in aerobic physicalactivity and lowering of stress levels [7]. If patientsdo not respond to this approach during two tothree cycles, the introduction of an SSRI wouldseem to the treatment of choice, either to be takenintermittently or during the complete cycle. Interms of cost-effectiveness the initial treatmentshould be given during the luteal phase and, if noresponse is obtained, a daily dose may be pre-scribed. In the event of non-response to SSRItreatment, the introduction of therapy with GnRHmay be required despite the possible side effects.

Cognitive-behavioural psychotherapy, whoseefficacy has been shown in different studies[44–46], can be proposed as adjuvant therapy.

In conclusion, PMDD is a complex clinicalsyndrome which is notoriously difficult to treat.Nevertheless, a well-defined therapeutic strategyshould enable the majority of women to obtain re-lief from their symptoms.

With special thanks to Mrs R. Sudan for editorialassistance.

Correspondence:Dr Francesco Bianchi-DemicheliClinic of Infertility and Gynaecological EndocrinologyDepartment of Obstetrics and GynaecologyGeneva University Hospitals32, Boulevard de la CluseCH-1211 Geneva 14E-Mail: francesco.bianchi-demicheli@hcuge.chfbianchi@worldcom.ch

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